Health & Disease - NYAS

This new conference will showcase advances in biomedicine and how they are translating to better treatment options, as well as new avenues for research.

Published March 23, 2016

By Diana Friedman

The New York Academy of Sciences and The Sohn Conference Foundation today announced the inaugural Sohn Conference: Pediatric Cancer in a Post-genomic World, taking place March 30 to April 1, 2016 in New York City. Sponsored by The Sohn Conference Foundation, this conference is the first of its kind to convene leaders in the global pediatric cancer community to share latest developments in research and treatment.

“The Sohn Conference Foundation has brought together elite thought leaders in the global investing community for more than 20 years, and with the launch of this conference in partnership with The New York Academy of Sciences, we strive to do the same in the pediatric cancer space. By breaking down the silos of science and encouraging the industry to collaborate on advancements in research, we can bring life-saving treatments to children battling cancer across the globe,” says Evan Sohn, Vice President, The Sohn Conference Foundation.

The Leading Cause of Death

In the United States, cancer is the leading cause of death by disease for children and globally, more than 250,000 children are diagnosed with cancer each year. Advances in cancer research and treatment have helped more children survive into adulthood, but have also underscored the need for more precise therapeutic options for this vulnerable population. Further, because the genetic profiles of children are less complex than adults, pediatric cancer research is critical not only to children, but to efforts that will unlock the cure for other cancers.

This 2 1/2-day conference will convene leading researchers, clinicians, pediatric cancer advocates, and industry and governmental stakeholders from around the world. The highly-regarded speaker lineup includes scientists who are on the forefront of pediatric cancer research, who will discuss the latest biomedical advancements that will have a tangible impact on children fighting cancer.

“It’s tremendously exciting to be part of this important meeting. The speaker list is a real ‘Who’s Who’ of the leaders in paediatric cancer genomics. The timing for this meeting that will bring the world’s thought leaders together to discuss and debate how best to bring the amazing advances we have made in the lab to the bedside of children with cancer is perfect,” says Richard Gilbertson, MD, PhD, Director, Cambridge Cancer Center, The University of Cambridge. “I am looking forward to the science that will be presented and discussed as well as the ripples of progress that will spread out long after the last talk is over.”

Bridging Genomics and Immunotherapy

Gilbertson will kick off the conference with a keynote speech on “The Successes and Future Direction of Pediatric Cancer Research and Therapy.” Craig B. Thompson, MD, President and CEO, Memorial Sloan Kettering Cancer Center, will present a second keynote speech on “The Role of Epigenetic and Metabolic Mutations in Stem Cell Maintenance and Pediatric Cancers.”

The conference agenda includes sessions on emerging cutting-edge basic and clinical research in epigenetics, mechanisms of metastasis and disease recurrence, disease risk factors, and diagnostics in pediatric oncology, as well as novel therapies and strategies to improve clinical development and treatment access.

“Bridging the fields of genomics and immunotherapy together is our greatest hope,” says conference speaker and member of the scientific organizing committee John Maris, MD, Pediatric Oncologist, The Children’s Hospital of Philadelphia and University of Pennsylvania, of his work on neuroblastoma, the most common extracranial solid tumor in childhood. “We will be increasingly individualizing therapy based on the unique features of the patients and their heritable genome and the evolving cancer genome/proteome. The road to translating research findings into novel therapies is long, but we’re working on it.”

Also read: The Latest Advances in Pediatric Cancer Research

Uncovering New Breakthroughs in Addiction Research

A graphic featuring the outline of a human head with different pills/medications scattered about.

Nora D. Volkow and George K. Koob describe how research in biomedical science illuminates the puzzle of addiction, specifically the role of neurobiology.

Published March 15, 2016

By Diana Friedman

Image courtesy of adragan via stock.adobe.com.

Expanding addiction studies to include the brain has been challenging for researchers, despite promising results on the neurobiological aspects of addiction. Recently we spoke with two of the speakers from the upcoming event “The Addicted Brain and New Treatment Frontiers: Sixth Annual Aspen Brain Forum,” Nora D. Volkow, MD, of the National Institute on Drug Abuse (NIDA), and George F. Koob, PhD, of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Here, they described how research in biomedical science illuminates the puzzle of addiction.

How would you expect that new knowledge gained from major initiatives from the NIAAA and the NIDA will help to move forward national efforts to improve prevention, treatment, and policies on addiction issues?

George F. Koob:

A significant milestone was the identification of a framework for the three stages of the addiction cycle (intoxication, withdrawal/negative affect, and craving), which represent neuroadaptations in three neurocircuits. This knowledge provides multiple viable targets for medications to return disrupted neurocircuitry to homeostasis and promote recovery. At the NIAAA, our hope is that our longitudinal research programs will converge to provide us with both genetic and environmental factors that will allow us to promote resilience and avoid vulnerability to alcohol-related problems. We know there is high genetic hereditability in alcohol use disorders but that one is not condemned to contracting a disorder. The current work will allow us to identify what environmental factors exacerbate or remove vulnerability.

Nora D. Volkow:

Addiction is a disease of the brain. So, just like any other disease–cancer, diabetes, or asthma–the more we know about the etiology and trajectory of the disorder, the smarter and more targeted the approaches we will be able to develop. This research helps us, among others, identify promising targets for the development of medications and other treatments.

And this focus will also lead to a better understanding of the factors that influence the trajectory or course of the disease such as genetics and epigenetics, comorbid conditions, social support, treatment access and availability, and social stigma. We are constantly improving the quality of this information, which is helping us translate it into more effective and personalized prevention and treatment interventions.

What are some of the significant obstacles that you have encountered in your research over the course of your career? How have you sought to overcome these hindrances?

George F. Koob:

The biggest obstacle in my research work, was, and remains a misunderstanding of the addiction process. Addiction is a brain disease and more importantly it is a disease of the brain motivational systems. However, motivation comes from two sources: positive reinforcement and negative reinforcement. To a large extent convincing the scientific community of the negative reinforcement piece has been a challenge.

I like to say that I spent the first half of my career trying to understand how we feel good and the second half of my career trying to understand how we feel bad. We now know that what I call “motivational withdrawal” (comprised of a reward deficit and a stress surfeit) is a critical part of the addiction cycle and a key part of the neurocircuitry driving compulsive drug seeking and drug taking.

Nora D. Volkow:

I began my research career at a time when brain imaging techniques were emerging and providing us, for the first time, the ability to study the human brain’s function and neurochemistry noninvasively. I immediately saw that brain imaging offered a unique opportunity to investigate how drugs affect the human brain and how these changes influence behavior. However, it took us several years to convince the scientific community that the brain of cocaine abusers showed evidence of cerebrovascular toxicity, a finding that now has been corroborated by multiple clinical and preclinical studies.

But, even more challenging was the stigma I had to face regarding my interest on addiction. I had to convince my colleagues of the value and importance of studying the neurobiology of addiction, which was viewed by many, including some scientists and physicians, as a moral failure, thus undeserving of my efforts to use modern medical methodologies to study it.

Are there specific moments from your career that you are particularly proud of, or that stand out to you?

George F. Koob:

I am particularly proud of having trained 80 postdoctoral fellows, most, if not all of whom worked in science for their careers. I am also proud of pushing “the dark side of addiction” and weaving the frameworks of opponent process, stress and self-medication back into the fabric of our understanding of the addiction process.

Nora D. Volkow:

My proudest moments have always been when an addicted person, or their relatives, contact me to thank me for giving them a better understanding of what they or their loved ones are going through, and for giving them hope that their disease can be treated.

Also read: Teaming Up to Advance Brain Research

Improving Clinical Trials through Mobile Technology

Mobile technology is emerging as a powerful tool for transforming the way clinical research is conducted now and in the future. Acquisition of real-time biometric data though the use of wireless medical sensors will allow for around-the-clock patient monitoring, reduce costly clinic visits, and streamline inefficient administrative processes. With the promise of this technology also comes challenges including digital data privacy concerns, patient compliance issues, and practical considerations such as continuous powering of these devices.

This podcast provides an illuminating examination of both the promises and challenges that underpin the implementation of mobile technology into the clinical realm.

Advances in Molecular Medicine Led to Better Cancer Treatment

A doctor wearing a suit and tie poses for the camera while seated behind his desk.

Lewis Cantley’s discoveries in the laboratory are changing the way we think about and treat cancer.

Published June 1, 2015

By Siobhan Addie, PhD

The 2015 Ross Prize in Molecular Medicine was awarded to Lewis C. Cantley, PhD, who serves as the Margaret and Herman Sokol Professor in Oncology Research and the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital. Dr. Cantley received the award at a scientific symposium held at the Academy on June 8, 2015, in his honor.

Early in his career, Dr. Cantley discovered phosphatidylinositol-3-kinase (PI-3K), an enzyme that is important for cell growth, insulin signaling, and immune cell function. Dr. Cantley’s discovery has led to one of the most promising avenues for the development of personalized medicine. Currently, Dr. Cantley’s lab is investigating new treatments for diseases that result from defects in PI-3K and other genes in this important metabolic pathway. He shared his thoughts on this prestigious award as well as the past, present, and future of cancer treatment.

What is the current focus of your laboratory?

My laboratory is trying to understand why cancer cells have altered metabolism and take up significantly more glucose than normal cells. I initially became interested in this area following our discovery of phosphoinositide-3-kinase (PI-3K), an enzyme that is important for cell growth. We came to the realization that when PI-3K is activated, cells consume glucose at significantly higher rates, which is consistent with the Warburg Effect, first described decades earlier by Otto Heinrich Warburg. [The Warburg Effect is the observation that cancer cells produce the majority of their energy by glycolysis and lactic acid fermentation, as opposed to oxidation of pyruvate in mitochondria, as is observed in healthy cells.]

Mutations in PI-3K and other metabolic genes can cause cancer cells to take up increased amounts of glucose, and understanding this process will hopefully reveal new targets for cancer therapies. Together with Craig Thompson and Tak Mak, I co-founded a company called Agios Pharmaceuticals to further explore this concept. Independent of Agios Pharmaceuticals, my lab continues to investigate the mechanisms of altered cancer cell metabolism, and it is our goal to develop cancer drugs for the targets that we discover.

Who were your role models in science and how did they inspire you?

Harold Varmus and Michael Bishop were two of my major role models because of their elegant studies on how viruses cause cancer. It was this work that led to the realization that cancer is caused by mutations in human genes. It was paradigm-shifting science because it made us understand that cancer is driven by sporadic mutations in DNA and that the changes in metabolism that Otto Warburg originally observed were a consequence of mutations in genes (like PI-3K) that control metabolism through complex signaling networks.

What led to your discovery of PI-3K?

The discovery of the Warburg Effect made scientists examine changes in cancer cell metabolism. Much of the 20th century was spent trying to understand how cancers change their metabolism, specifically how they perform anabolic processes at a higher rate. In the late 1970s and early 1980s, work from a number of labs led to the discovery of important oncogenes. In our early work we used viral oncogenes to discover PI-3K.

By immunoprecipitating oncoproteins we were able to isolate PI-3K, and at first we believed PI-3K was producing the well-known lipids, PI(4,5)P2 or PI(4)P. However, once we characterized the product, we found out it was chemically distinct from the two well-known phospholipid forms in that the phosphate was on the 3 position of the inositol ring rather than the 4 or 5 position. We were extremely excited since this species had never previously been described.

Upon your discovery of PI-3K, did you realize how complex the signaling cascades were?

Our work revealed that PI-3K phosphorylates the 3 position of phosphatidylinositol; however, after that initial discovery we realized that many other phosphorylation combinations could be generated by PI-3K. Sure enough, in subsequent years, a whole new group of lipids was discovered, including PI(3)P, PI(3,4)P2, PI(3,5)P2 and PI(3,4,5)P3, although at the time it was not clear what they were doing. Now we know that many of these lipids are important in cells for controlling protein kinase cascades and actin rearrangement, which is critical for cell movement.

I was extremely excited by the importance of PI-3K for human disease. Initially our team was mainly focused on insulin signaling rather than on cancer, but soon we realized that there were commonalities between insulin signaling and the evolution of cancers. The story of PI-3K has certainly turned into a bigger story than I could have ever anticipated.

PI-3K inhibitors work quite well in blood cancers, but show more variable results in solid tumors. Why do you think that is?

The PI-3K gene that is mutated in solid tumors (PIK3CA) encodes the same enzyme that insulin activates so inhibitors of this enzyme cause insulin resistance resulting in hyperglycemia, which limits the dose of drug that can be used for therapy. In contrast the PI-3K inhibitor that was approved for treating B cell lymphomas, idelalisib, targets the enzyme encoded by PIK3CD, which does not mediate insulin responses. Thus there is less toxicity and higher doses of drug can be achieved, allowing more effective killing of tumor cells.

I also think that the total number of cancer cells in the body at the time a patient goes on therapy has a major role in explaining resistance to therapy. We now know that there is tremendous heterogeneity in the mutational events in most solid tumors and the more cells present, the more likely that a few cells in the tumor will be resistant to the therapy. That is why we are exploring the usefulness of neo-adjuvant therapy, the delivery of an anticancer drug prior to surgery. Another option for improving patient outcome is adjuvant therapy, the delivery of an anticancer drug immediately following surgery, even before recurrence is detected.

Generally, when metastatic cancer is diagnosed, the total number of cells in the body can be massive. Bert Vogelstein aptly pointed out that every time a cell divides there is a chance for an error in DNA replication, resulting in genetic aberrations, and the more times that happens the greater the diversity of mutations in the tumor and the lower the probability that a single agent will kill all cells in the tumor. Initial clinical trials in solid tumors are typically done in patients who have metastatic disease and have failed multiple therapies—it’s a high bar to achieve complete responses in this setting.

Why do certain cancer drugs look quite promising in pre-clinical models yet do not perform as well in humans?

New cancer drugs are often tested in mice that have a single, small tumor. Since the tumors in mice contain relatively few cells, the odds that we can kill all those cells are rather good. The clinical setting with human patients is far more challenging and complex because, as I indicated before, human cancer cells have greater genetic diversity and there are at least 100 times more cells than in a mouse tumor.

That is not to say that mouse models are bad, but we need to pay better attention to the mathematics. In normal preclinical studies we give seven mice the experimental drug and seven mice receive the placebo. As pointed out by Bert Vogelstein, these numbers are far too low. We need to increase the number of animals used in preclinical studies and focus on therapies that cure all the mice, then we are far more likely to find drugs or drug combinations that are also effective in humans.

If you had a crystal ball that showed you the future of cancer research and treatment, what would you like to know right now?

That’s a tough question! One of the things I would like to know is whether we will have technologies available in the future to detect circulating mutant DNA at very early stages of disease. I think it would be great to have a test that would allow us to intervene with therapies potentially even before a tumor can be felt by a patient or detected by standard imaging techniques.

A test like this would have to be extremely sensitive so that we could detect extremely low levels of circulating mutant DNA. We know that we can pick up circulating mutant DNA in the case of metastatic disease, but it would be fantastic to do this for very early stages of cancer.

Your clinical test sounds like a fantastic idea—what are the pros and cons?

If we were able to develop a test like this and it were cost-effective, it could very well become a routine clinical procedure that takes place during the annual physical every year after the age of 50. If people are at high risk for cancer, they could have the test done starting at age 30. These test results could potentially tell you that you have circulating copies of oncogenic mutant DNA. I believe that if clinicians administered targeted cancer therapy at these early stages of disease, we would have a much higher likelihood of a cure.

The success of this whole plan depends on the development of targeted cancer drugs that are safe and have few off-target effects. Developing these drugs and testing their safety could take as long as 5–10 years. Most of the drugs we currently use for cancer therapy would not be acceptable to use in this setting since they could cause more harm than good and even cause new cancers to occur.

Another caveat to this blood test is the possibility of false positive results, where patients may show the mutant DNA but never actually progress to full-blown disease. I think that personalized medicine is the future. If we truly want to cure cancer, we need to target the cancer cells more effectively and hit them earlier with safe, non-toxic drugs.

PI-3K is at the interface of insulin signaling and cancer; what is the relationship between these two?

Many types of cancer cells express higher levels of insulin receptor (IR) or insulin-like growth factor 1 receptor (IGF1R) than the tissue from which they evolved. If a patient with this type of cancer becomes insulin-resistant, as could happen from a high-sugar, high-carbohydrate diet, there will be high levels of circulating insulin and IGF1in the blood.

his is a very dangerous situation because if the tumor expresses IR or IGF1R, it will be getting a strong signal for activating PI-3K all the time, even if PI-3K is not mutated. This will drive tumor growth and may render the tumor less vulnerable to chemotherapy. If I had a cancer that expressed high levels of IR or IGF1R I would go on a low-carbohydrate diet the very next day.

High levels of dietary sugar can cause insulin-resistance, which results in near-constant elevation of circulating insulin. We know that insulin activates PI-3K, which is almost certainly driving a large fraction of cancer growth. In the United States there is a very high fraction of people who are insulin-resistant, but many of them are undiagnosed. It is a frightening possibility that we will retrospectively regret making sugar cheap and broadly added to foods the same way we now regret making cigarettes cheap and broadly available 70 years ago.

What does winning the Ross Prize in Molecular Medicine mean to you?

I am tremendously honored and excited to win the Ross Prize. I am particularly grateful for this award because it is not given for a single discovery, but rather a body of work where a discovery has been translated into a clinical outcome. That is difficult to do; but I certainly did not do that alone. Hundreds of people collaborated with me at various stages—from the mouse models, to the biochemistry, all the way to carrying out a clinical trial. I have been very fortunate in my career to work closely with passionate people who are focused on a common goal of identifying new cellular targets for cancer drugs.

About the Ross Prize in Molecular Medicine

The annual Ross Prize in Molecular Medicine was established in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine. The winner is an active investigator who has produced innovative, paradigm-shifting research that is worthy of significant and broad attention in the field of molecular medicine. This individual is expected to continue to garner recognition in future years, and their current accomplishments reflect a rapidly rising career trajectory of discovery and invention. The winner receives an honorarium of $50,000.

Climate Change from a Human Health Perspective

An array of screens related to climate science.

Experts gather in Barcelona, Spain, to explore the consequences of climate change on human health.

Published April 30, 2015

By Diana Friedman

The New York Academy of Sciences, in partnership with the “la Caixa” Foundation and BIOCAT, will host a 2-day conference, Human Health in the Face of Climate Change: Science, Medicine, and Adaptation, on May 14-15, 2015 in Barcelona, Spain.

“The threat of climate change to health will take many forms – from a more dangerous physical environment to the worsening quality of air and water to the spread of infectious diseases,” says Christopher Dye, DPhil, FMedSci, FRS, Director, Strategy, Office of the Director General at the World Health Organization, as well as a conference organizer and keynote speaker.

The conference is being convened in light of new research that seeks to provide a deeper understanding of the health consequences of climate change on humans – including better quantification of these effects – to improve health preparedness and protect vulnerable populations.

“Many infectious and non-communicable diseases are climate sensitive. They may be associated with specific seasons; respond to extreme events such as droughts, heatwaves, or flood; or shift in their distribution according to shifts in the long-term climate,” says Madeleine Thomson, PhD, Senior Research Scientist, International Research Institute for Climate and Society at Columbia University, as well as a conference organizer and speaker.

Empowering the Health Community

“Climate knowledge and information can be used to understand, predict, and better manage climate-sensitive health outcomes and can also help us to assess the impact of many health interventions. With a changing climate, understanding these connections and empowering the health community to use this knowledge is key to effective adaptation,” adds Thomson.

“We need to move forward effectively and quickly as our actions as humans are moving our climate to dangerous and unprecedented states that will for sure exert a strong pressure on the health status of people globally,” says Xavier Rodó, PhD, ICREA & Catalan Institute of Climate Sciences (IC3), as well as a conference organizer and speaker. “We need new science that teaches us how to face and respond to this challenge. This conference attempts to highlight those areas that require new science, as well as methods to spur policymakers into action by working together,” adds Rodó.

Topics to be explored at this multidisciplinary conference include: changes in the distribution of extreme climate events, vulnerability due to extreme weather events, land-use change and agricultural production, variable epidemiology of parasites and infectious diseases, and climate-altering pollutants.

The conference is designed to be of interest to climate scientists, atmospheric/oceanic scientists, ecologists, evolutionary biologists, epidemiologists, public health specialists, and policymakers, among others, as well as members of the media.

“The impact on human health is among the most significant measures of the harm done by climate change – and health can be a driving force for public engagement in climate solutions,” says Dye.

Also read: Climate Change and Collective Action: The Knowledge Resistance Problem

The Caped Crusader for Better Mental Health Outcomes

An illustration of a superhero overlooking a city skyline as his cape blows in the wind.

Andrea Letamendi, PhD, discusses the value of addressing mental health issues through the lens of beloved fictional narratives.

Published July 24, 2014

By Diana Friedman

Image courtesy of rudall30 via stock.adobe.com.

In honor of Batman’s 75^th anniversary, DC Entertainment declared July 23 Batman Day. What does this have to do with science? More than you might expect, with a little imagination. For psychologist Andrea Letamendi, PhD, the Batman world, with its roster of criminally insane villains, is a fictional window onto very real issues. Her podcast series, The Arkham Sessions (named for the asylum where Batman’s enemies usually wind up after the hero thwarts their plots) analyzes characters and interactions from Batman: The Animated Series to explore subjects such as coping with trauma, mental disorders, patient treatment, and stigmatization of people with mental illnesses.

According to National Library of Medicine historian Dr. Michael Sappol, “It’s a powerful technology for forming public opinion. It [doesn’t] just reason with the audience, it recruit[s] the audience’s emotions.” Dr. Letamendi leverages a balance between that emotional resonance and the relative security of fiction to engage her audience in consideration of challenging themes. “It’s a way to educate people about psychological science and address important topics in a way that feels safe—less threatening or less personal,” she says. “At the same time, many people feel very connected to these fictional narratives and the stories actually help us to tune in.”

Dr. Letamendi spoke with The New York Academy of Sciences (the Academy) from Comic-Con in San Diego about superheroes and psychology.

Why apply psychological analysis to fictional characters?

As a psychologist, I’m invested in broadening public knowledge about the psychological sciences. I find that one way I can do that is to speak to my passion and the passion of many others: comic books, science fiction, and fantasy. I’ve had wonderful opportunities to speak at universities and at Comic-Con and other cultural conventions to utilize these narratives that people can really relate to—the stories, heroes, and villains that people already know—to examine important health issues. It’s fun but it’s also an educational advantage.

Are there useful parallels between cartoon characters and real people?

Yes! For example, my first experience speaking on a panel was talking about how comic book heroes are actually really similar to real life heroes, specifically soldiers who have experienced combat-related trauma. I used to practice at a veterans hospital and have a lot of experience working with soldiers and veterans returning from Iraq and Afghanistan with physical and psychological injuries.

The panel was a chance to talk openly about the impact of recent wars on the people who fight in them, and how the field of psychology is struggling with how to meet the needs of the men and women coming back from those conflicts. It’s a really serious topic, but we can draw upon these fictional narratives that simulate and evoke real tensions and interests in a way that feels safe and remains relatable.

How does your series, named for the Arkham Asylum for the Criminally Insane, avoid associations between mental illness and criminal behavior?

It’s really important to us to always make that distinction. When we started the show we knew we’d be examining the psychology of a lot of villains, but we’re not just trying to come up with labels or diagnoses for them. Every episode of the Batman series has a lot of psychological elements to it. We end up talking about such a wide range of subjects—memory loss, substance abuse, anxiety, family issues, patient care and hospitalization, childhood trauma.

We speak about these issues in a way that deliberately doesn’t stigmatize, but rather helps to normalize these experiences. The result is that we’re very inclusive in a way that let’s everyone relate. We include Batman in our analyses, not just villains, and he’s a character with a lot of issues as well. My hope is that it combats the idea that people with mental health problems are villains or criminals.

Do you have a favorite character?

I like the villains who are overlooked because they’re just seen as being big and burly, like Killer Croc or Clayface. They’re like onions. When you unravel them you realize there’s a deep psychological history and trajectory there that got them to where they are [by the time you meet them in the series].

Are there lessons from Gotham City that might apply to real cities’ policies on mental health care?

There are real barriers to appropriate, evidence-based care. In big cities with diverse populations, we deal with issues of underserved populations that don’t have access to care. There are groups of people with structural and psychosocial barriers to getting care. Sometimes we struggle to provide care that’s culturally or linguistically appropriate. We need to think about all of these psychosocial elements to ensure that people have opportunities to heal.

Any parting thoughts?

It is Comic-Con week! If you’re coming, please keep in mind that you can put together a curriculum of educational panels on really interesting topics like psychology, underrepresentation, and gender equality. Comic-Con is fun and a celebration of superheroes, but it’s also an opportunity for education and to demystify and reduce some of the myth around science.

Also read: From Imagination to Reality: Art and Science Fiction

Research Paves the Way for Novel Drug Development

A gloved hand holds a medical syringe loaded with medicine.

Scientists at the University of East Anglia have figured out a flaw in bacterial armor, potentially paving the way for novel drug development at a time when antibiotic resistance is becoming a critical global health problem.

Published June 26, 2014

By Diana Friedman

Image courtesy of bonnontawat via stock.adobe.com.

According to the World Health Organization, “antibiotic resistance—when bacteria change so antibiotics no longer work in people who need them to treat infections—is now a major threat to public health.” In short, disease-causing microbes are evolving molecular countermeasures to drugs at a far faster rate than we’re discovering new interventions.

However, a group of scientists at the University of East Anglia recently scored a point for Team Humans by mapping the structure of a protein used by a large class of bacteria to construct a defensive outer membrane. Gram-negative bacteria cause a swath of illnesses including pneumonia, salmonella, meningitis, and bloodstream and wound infections. They’re also exceptionally difficult to kill because the outer membrane provides protection from immune cells and antibiotics.

A key component of this natural armor is a molecule called lipopolysaccharide, which gets delivered to its place in the protective layer by transporter proteins called LptD and LptE. Researchers at UEA collaborated with scientists at the Diamond synchrotron to blast these transporters with super high-powered x-rays, the diffraction pattern of which reveals the atomic structure of the protein.

The Atomic Blueprint

When it comes to proteins, form and function go firmly hand in hand. Using the atomic blueprint as a guide, the team was able to model the function of the LptDE complex.

“We have identified the path and gate used by the bacteria to transport the barrier building blocks to the outer surface. Importantly, we have demonstrated that the bacteria would die if the gate is locked,” says lead researcher Prof. Changjiang Dong in this press release. “If the bacteria do not have the outer membrane, they cannot withstand environmental changes. It also makes it easier for the human immune system to kill them.”

Now that researchers understand the structure and mechanisms of the bacterial defenses, it may be possible to develop drugs to interfere with their function. “The really exciting thing about this research is that new drugs will specifically target the protective barrier around the bacteria, rather than the bacteria itself,” says study author Haohoa Dong. “Because new drugs will not need to enter the bacteria itself, we hope that the bacteria will not be able to develop drug resistance in the future.”

It’s too soon to say, but at least it’s a start.

Also read: New Scientific Approaches to Antibiotics in Food

Research Leads to New Treatments for Immune Diseases

Models of different atoms and molecules.

John O’Shea turned his passion for clinical care into a successful research career focusing on understanding the molecular basis of cytokine action, with the aim of providing better treatment options for patients.

Published June 1, 2014

By Diana Friedman

John O’Shea, MD, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, NIH, has pushed the frontiers of molecular medicine during his career through research that has led to new treatments for immune diseases. He was named the 2014 winner of The Ross Prize in Molecular Medicine, which honors researchers whose discoveries change the way medicine is practiced.

How did you get involved in studying immunology?

I was drawn to immunology after admitting a veteran to the hospital, who had vasculitis and, sadly, died of this illness. At the time, the NIH was the center for research on vasculitis, so that’s what ultimately led me to join the NIH for training beyond internal medicine.

I initially worked on complement receptors and then the T cell receptor in my postdoctoral training at the NIH. When I set up my own lab, the importance of tyrosine phosphorylation as a first step in signal transduction was becoming increasingly apparent. We therefore set out to find kinases expressed in lymphocytes and cloned one of the Janus kinases, right around the time it was becoming clear that this family of kinases was critical for cytokines.

Why are cytokines so exciting as a research focus?

Cytokine signaling is of particular interest to me because it is a very basic problem: how cells respond to external cues. What is exciting is that the pathway is an evolutionarily ancient one employed by Dictyostelium and everything from insects to mammals. Advances from all these diverse organisms and models are valuable in understanding the basic problem. Equally, though, these insights often are directly relevant to patients with immune-mediated disease.

What questions are you currently trying to answer?

We remain very interested in how cytokine signals cause cells to grow and differentiate. What that means to us now is how external cues impact epigenetic changes and how this relates to control of gene expression. Of course, “genes” means more than just classical protein coding genes, so we are also interested how microRNAs, lncRNAs, and eRNA are all regulated by cytokines.

We are also interested in how Jak inhibitors do or do not work in patients with autoimmune disease. Will second generation selective inhibitors be as effective and be safer or not? What is the best way to use these new drugs, and for which diseases?

How has the field of molecular immunology changed since you started—and how will it continue to change?

Image courtesy of alice_photo via stock.adobe.com.

What is most different about doing science now versus a decade or two ago is that today many experiments are set up in a way that the denominator is often the entire genome or products of the entire genome. More and more this will be the case, and as such the analysis of the data becomes increasingly complex. We will be perturbing cells in many of the same ways, but the analysis will be vastly more complex and comprehensive. We will also use single cells and not heterogenous populations of cells, adding yet more complexity to the analysis.

But the basic question we are still trying to answer—how cell behavior is changed by external cues—is not so different from the one we began asking decades ago. What is astonishing is how these questions can now be answered.

How important is collaboration in the field of molecular medicine?

I have had very edifying interactions with industry scientists over the last 20 years with the outcome that patients with rheumatoid arthritis have a new treatment option. These people are experts in making treatments a reality and they are essential to moving the field forward.

Additionally, the NIH has been an extraordinary place to work. From my first experiences, the support from so many colleagues has been astonishing. One really feels like the only limitation to discovery is one’s creativity and ability. It is troubling at a time when so much could be done to really understand basic biological processes and mechanisms of human disease that funding is limited. This is a loss on many levels, but most of all a loss for patients with debilitating diseases.

The other big plus of place like the NIH is the ability to move from very basic problems directly to the bedside and back again. This was a common occurrence during my training—physicianscientists moved from one realm to the other.

Do you think that medical education currently has enough of an emphasis on research?

I worry that at a time like this, when there is so much opportunity, that we are not doing everything we can to foster the development of physician-scientists and translational basic researchers. At the same time, physicians-in-training have so much to learn these days—the amount of knowledge that students in medical school have access to now, and need to absorb, is just astronomical compared to what it was in my day; not to mention there is also the technology they have had to become proficient in using, and complex societal changes that have taken place. So working as a team, with people with different specialties and knowledge sets becomes increasingly important.

What does winning The Ross Prize mean to you?

Being that the prize is focused on molecular medicine, it is very gratifying—this is exactly how I think about myself in terms of my career focus. It’s very humbling, but also very exciting because that’s sort of what I was hoping to accomplish from the start —to make discoveries that are important scientifically, but also directly help people. For me, it doesn’t really get any better than that.

About The Ross Prize in Molecular Medicine

The Ross Prize in Molecular Medicine was established in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine. The Ross Prize recognizes biomedical scientists whose discoveries have changed the way medicine is practiced. The prize is awarded to midcareer scientists who have made a significant impact in the understanding of human disease pathogenesis and/or treatment and who hold significant promise for making even greater contributions to the general field of molecular medicine.

A New Model for a Career in Industry

A graphic diagram of a man hold his chest, presumably a heart condition.

Biophysicist Mark Kaplan explores a fast-track to bring innovation to patients.

Published June 1, 2014

By Hannah Rice

Image courtesy of Sebastian Kaulitzki via stock.adobe.com.

For Mark Kaplan, a biophysicist who chose industry after his postdoc, the appeal of science lies in its predictability. From an early realization that he could position the stars and planets by studying astronomy—and check his predictions peering through his own telescope—to his work in drug discovery, his interest has drawn on a fascination with tracing the logic behind phenomena and harnessing it to answer questions.

“There are those who are more motivated by ideas and those more motivated by problems; there’s a relationship between the two, but I found myself more attracted to solving problems than to exploring ideas,” Kaplan says. “That’s what motivated me to take a leap and get my first job in industry.”

Kaplan is now a senior principal scientist at Pfizer’s Centers for Therapeutic Innovation (CTI) New York, a new facility at the Alexandria Center for Life Sciences, where he works with academic research labs to design drugs in several disease areas. In December 2012 Kaplan brought his work on myocardial infarction (i.e., heart attack) to The New York Academy of Sciences, co-organizing a successful Hot Topics in Life Sciences symposium that explored investigational treatments such as cell-based therapies and strategies to preempt heart damage.

Finding Drug Discovery

But when Kaplan tried to organize an astronomy club in junior high school, he was disappointed by the response: “Being the nerd that I was, I couldn’t understand why that many other people weren’t interested,” he says.

“One particular aspect that always struck me is that when you look at the stars you’re also looking back in time: the light that you’re seeing was emitted hundreds or thousands of years ago. The star that you’re looking at could have blown up and given the vast distances of space you won’t know it.”

Despite this vastness, we can study the stars and watch as their movements validate our models. In high school, Kaplan was drawn to this same predictability in the periodic table of elements. And eventually, as he began searching for patterns that govern life, he became interested in understanding “life as a chemical reaction,” explaining how biochemistry can “give life, make things alive, and give you memory and emotion.” Although Kaplan recognizes that this depiction is perhaps too reductionist, it’s a quest that intrigues him.

Kaplan studied biochemistry at Harvard as an undergraduate and pursued a PhD in biophysics with a focus on radiation biology at the University of California, San Francisco. As a postdoc studying the genetic basis of cancer at the University of Wisconsin–Madison, he looked at what happens when a specific DNA repair mechanism is inhibited. Cells repair DNA after it is damaged by exposure to environmental insults such as radiation, and errors in DNA that are not corrected can lead to cell growth abnormalities. This time, Kaplan could design experiments to target a particular section of DNA in the lab, and then find out how the modifications affect a living animal using gene-knockout technology.

A Career in Industry

After completing his postdoc, Kaplan decided to work in industry because of its focus on translating research into solutions for patients. He says he realized that “if your motivation is to solve problems, then industry is probably a better place for you.”

Today, Kaplan works with a staff of 25 at CTI-NY, which is not intended to replace the traditional pharmaceutical model, with thousands of researchers on a campus shepherding medicines from inception to large-scale clinical trials and rollout. Instead, it serves as a bridge between academia and industry, and its scientists look for ways to speed the transition from “a really interesting scientific discovery [to] a new compound and a new medicine.”

Although his background is in oncology, Kaplan is leading a team of scientists to develop drugs for cardiovascular disease, and he says that this flexibility is central to the CTI strategy. CTI is “disease agnostic,” meaning that researchers are not focused on a specialization but are instead searching for agents that seem particularly promising for medical uses.

Their approach involves working closely with experts in the field at research institutions, and CTI-NY is designed to be conducive to such collaboration—it’s centrally located in NYC, it provides lab space on-site, and project leadership is shared between a university PI (a professor) and principal scientist at Pfizer. The idea is to create an equal partnership, so intellectual property is also co-owned and academics can present results in medical journals.

A Shift Toward Greater Openness

The pharmaceutical industry has shifted away from a “closed system” toward greater openness; a “striking emphasis on external innovation” now prevails, Kaplan says. Previously, companies pursued therapies created by their own scientists, but they are now seeking to “access the scientific breakthroughs that are occurring in the wider world,” which he thinks is an exciting change. The CTI model is replicated in other cities (Boston, San Francisco, and San Diego), bringing Pfizer staff into proximity with academic medical centers in these local areas. Kaplan explains that “being able to meet face to face is important for building trust and for making sure that goals are aligned.”

Drug discovery as a field is always racing to find new therapies: to contend with internal competition, to meet patient demand, and to keep up with itself by replacing drugs whose patents are ending. Although Kaplan wonders whether the “easy drugs” that can keep up with the growing costs of R&D have been found, he answers his own query by saying that if he thought so, he’d be in a different business. Kaplan thinks that large molecules such as monoclonal antibodies and antibody-drug conjugates hold the greatest promise for therapeutic advances in coming years, as well as cell-based therapies (stem cells), which when fully realized will be a “quantum leap in terms of what we can do for patients.”

Building Networks

Kaplan says, with a tinge of irony, that it’s “an interesting time to be a scientist in New York,” pointing in the next breath to the old Chinese curse, May you live in interesting times. There are fewer industry jobs in New Jersey, where big pharmaceuticals have traditionally been based in the metro area. But New York City is home to innovation that is driving research in new directions, with projects like CTI leading this effort. There is also a strong research base at universities, and smaller biotech companies and nonprofits are in vogue: “If you are actively managing your career and looking for exciting opportunities they’re absolutely there.”

The ability to take new directions often depends on leadership, and Kaplan is quick to acknowledge the role mentors have played in his career. He is particularly grateful to those who gave him independence to take on projects that didn’t always match his qualifications, allowing him to “go out and fail,” as he jokingly describes it. Indeed, Kaplan’s career is defined by adaptability. He calls his transition to new research areas at Pfizer “a great learning opportunity” and talks with enthusiasm about his experiences interacting with other scientists in CTI and academia. The Academy too serves as an important venue for cross-sector and cross-organization interaction, Kaplan points out; you could “run into professors you might want to collaborate with.”

In our hyper-connected world where sharing is the it verb, it’s perhaps no surprise that science has followed suit, with scientists from every sector and discipline looking for new ways to team up to find solutions for some of our most challenging diseases.

Changing the Game: Fighting Alzheimer’s Disease

A graphic representation of a damaged nerve or cell.

Inspired by his mother-in-law’s courageous, but heartbreaking battle, George Vradenburg has teamed up with the Academy to take on Alzheimer’s disease.

Published August 1, 2013

By Noah Rosenberg

A 3D-rendered medically accurate illustration of amyloid plaques on a nerve cell (Alzheimer’s disease). Image courtesy of Sebastian Kaulitzki via stock.adobe.com.

George Vradenburg’s resume reads like a roadmap to prototypical business success. He was Phi Beta Kappa in college and attended Harvard Law School. He later co-published a magazine and brokered deals for media giants like CBS, Fox, and AOL, founding two charities in his spare time. George Vradenburg, to be sure, is a man who seized his life and career by the horns.

But then it all changed. In the early ’90s, as his mother-in-law faded with Alzheimer’s disease, Vradenburg could only sit back idly, helplessly. “I saw the progress from paranoia to hallucinations to falls to institutionalization to the late stage where she was physically immobile and totally unaware of her surroundings and her family,” Vradenburg remembers. “It is not a long goodbye, not the romanticized long farewell. It is a horrid disease.”

Of course, Vradenburg and his family weren’t alone. Today, 36 million people struggle with the disease worldwide, and that number is expected to grow to 115 million by 2050. So Vradenburg was shocked to realize that Alzheimer’s research and treatment had long been stagnant, frozen in a frustrating holding pattern.

True to form, Vradenburg decided he needed to do something about it. He enlisted his screenwriter wife to develop plays about her mother’s battle with Alzheimer’s, but it didn’t take Vradenburg long to understand that the level of zeal he brought to bear on curbing the disease was practically unparalleled.

“I thought, ‘Why in the heck is there not a national strategic plan on this?’” Vradenburg recalls, still incredulous. “I was frustrated by the absence of urgency and passion. Everyone seemed to be conducting business as usual.”

Taking Action

Vradenburg set out to change the nature of the game. He partnered with the Alzheimer’s Association and, for eight years, put on an Alzheimer’s fundraising gala. From there, he formed a political action committee, an Alzheimer’s study group, and, in 2010, co-founded USAgainstAlzheimer’s, an education and advocacy campaign for which he still serves as chairman.

And now, nearly two decades after his mother-in-law’s death, Vradenburg’s Global CEO Initiative—a newly-formed private-sector committee designed to collaborate with the public sector, non-profit community, and academia—has joined forces with The New York Academy of Sciences in a next-generation, cross-industry collaboration, called the Alzheimer’s Disease and Dementia Initiative (ADDI), that will attempt to effectively combat the disease once and for all.

The CEO Initiative’s goals, after all, are directly aligned with the Academy’s own efforts. Launched in 2011, the aim of the ADDI is the translation of basic research about disease mechanisms into the development of new methods for diagnosis, treatment, and prevention of Alzheimer’s disease and dementia. The Academy developed a Leadership Council of multi-sector stakeholders—academic researchers, industry scientists, patient advocates, and government and foundation representatives—to define priorities and develop action steps for progress in Alzheimer’s diagnosis, treatment, and prevention.

Creating an Agenda

The Holy Grail for the ADDI is the development and implementation of a comprehensive research agenda aimed at preventing and treating Alzheimer’s by 2025. It is a bold, ambitious, and lofty goal—Vradenburg is the first to admit that.

But, he says, “I can’t be giving up. You have to continue to push ahead no matter how many failures there are.”

And so Vradenburg decided to support the ADDI and, in turn, the many multi-sector experts comprising the collaborative working group that dedicates its time and expertise to define key action items around big challenges: gaining a better understanding of the pathophysiology of Alzheimer’s; developing innovative therapeutic approaches and strategies to engage patients in clinical trials; decreasing the time, cost, and risk of drug development; and increasing funding models, such as public-private co-investment, social impact investment, and new public funding mechanisms.

The CEO Initiative generously seeded its partnership with the Academy with a contribution of $325,000. Academy President and CEO Ellis Rubinstein considers the gift “a testament to the power of the partnerships being facilitated by The New York Academy of Sciences.”

“George is a visionary who realizes that the complexity of the grand challenges confronting humanity can only be addressed efficiently through alliance-building,” Rubinstein says. “For this reason, we at the Academy regard George as a role model for budding philanthropists: he uses his resources not for self-aggrandizement but to catalyze collective action.”

The Path to 2025

The joint research agenda, to be developed by the Academy and the CEO Initiative by late summer 2013, is simply the beginning. The working group’s results will feed into the Academy’s upcoming conference, “Alzheimer’s Disease Summit: The Path to 2025,” to be held on November 6 and 7 at its Lower Manhattan headquarters.

The gathering will build on the work of the National Institutes of Health’s biennial Alzheimer’s Disease Research Summit and, according to the Academy, “advance a research agenda that is informed by the needs, experience, perspectives, and lessons learned from industry, academic, and government research efforts.”

Following the November summit, the working group will produce a meta-analysis, including long-term plans for patient engagement in clinical trials, preventative measures, and future coordination efforts.

Not one to chase progress timidly, Vradenburg cautions that the Academy and the CEO Initiative must use the fall Alzheimer’s Summit “not as a conversation but actually an action-driver. We need to use it as a deadline for taking certain steps.” To that end, he explains that the working group is expecting to reveal breakthroughs in the area of biomarkers, data-sharing, clinical trial recruitment, and innovative financing mechanisms during the summit.

Synergies Across Organizations

Vradenburg sees his partnership with the Academy as the logical path forward between two organizations whose objectives, and even personnel, have overlapped in the past.

“What intrigued me about the Academy was their reach—into academia and geographically,” he says, commending the Academy’s visionary leadership. “They have a reputation for taking on challenging issues. They have the same spirit of innovation and drive that I think I have, so there’s been sort of a mind meld at the leadership level.”

The feeling is mutual. “George brings an incredible energy to all of his endeavors,” says Academy Executive Vice President and COO Michael Goldrich, “which, combined with his formidable business acumen, makes him a person who gets results.”

A Critical Time

On top of that, the ADDI is embarking at perhaps the optimal time in the war against Alzheimer’s. This year, for instance, President Obama mentioned the importance of Alzheimer’s research in his State of the Union address—a sign of what Vradenburg calls a “significant uptick” in government attention to the disease. As a result, there has been “enormous progress” in research, he says, notably in the area of enhanced imaging techniques that allow for the detection of the disease up to 20 years before symptoms appear.

Progress, however, has been largely one-sided. “On the treatment side,” Vradenburg laments, “there have been zero advances.” This leads to a cruel reality in which patients might learn of their fate decades before it sets in, and with no way to prevent the disease’s onset.

“It’s frustrating for the patient population out there,” Vradenburg stresses. “They get treated with the wrong drugs; they’re wrongly diagnosed and mistreated at earlier stages.”

“And there’s also the second-hand victims, the caregivers,” he adds. “People are going bankrupt or having to quit work or delay college to care for their loved ones. There’s an emotional, physical, health, and financial impact of this disease on families around the world today.”

Exceeds $600 Billion Worldwide

In fact, the annual burden of caring for the current number of Alzheimer’s patients and those with related dementia exceeds $600 billion worldwide and will only continue to grow in the absence of meaningful innovation.

Vradenburg is aware, though, that success doesn’t come easy. He explains that the ADDI is pushing to introduce first-generation disease-modifying treatment into the marketplace by 2020 and to foster a means of prevention and effective treatment in the marketplace by 2025, as well as to develop the critical intervention methods to get treatment into the hands of at-risk populations.

“All of my efforts,” he emphasizes, “have basically challenged people to identify the critical hurdles that would change the trajectory and speed, the velocity and volume of what we’re doing. I’ve always got to be optimistic,” Vradenburg says.

Also read: Resolving Neuro-Inflammation to Treat Alzheimer’s Disease and Pain

About the Author

Noah Rosenberg is a freelance journalist in New York City.

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